The contribution of brain edema to raised intracranial pressure (ICP) in cases of traumatic injury remains a critical problem for which there is no effective clinical treatment at present. Elevations in intracranial pressure are a frequent cause of death, and result in a very poor prognosis in survivors. The long-term goal of this research is to elucidate those factors responsible for the development of traumatic brain edema. In the previous five years this laboratory has completely altered the thinking regarding the pathophysiology of this problem. We have introduced the new concept of a predominantly cellular edema after traumatic brain injury, as evidenced by a reduction of the Apparent Diffusion Coefficient (ADC) of water in magnetic resonance studies. This is in sharp contrast to the generally held view that edema is of vasogenic origin, secondary to blood brain barrier breakdown, extravasion of intravascular protein and osmotic movement of water into the brain Having identified the importance of cellular edema in TBI, this application will focus on the mechanisms responsible for traumatic cellular edema. We believe that this cellular edema is caused by disruption of ionic homeostasis and membrane pumps secondary to energetic crisis, which eventually leads to movement of sodium and obligatory water into brain. Moreover, we believe that this energy crisis, which occurs in the presence of adequate CBF, is associated with mitochondrial impairment as evidenced by reductions in N-acetyl- aspartate (NAA). Our four specific aims include utilizing newly developed flexible ion-selective K+ and Na+ electrodes to provide an accurate assessment of ionic shifts in diffuse and focal injury and how they are altered with hypoxia and hypotension. We will also measure the amount of tissue sodium and potassium associated with increases in brain tissue water and determine whether the net cation shift can account for all of the observed cellular edema. This will provide a basis for understanding the development of cellular edema and will reaffirm its major role of in the swelling process. Using each animal as its own control we will utilize non-invasive Magnetic Resonance Proton Spectroscopy (MRS) to rapidly assess the onset and degree of mitochondrial impairment in regions of cell swelling as reflected by changes in ADC, NAA and ATP as the injury evolves. We will confirm these measures at sacrifice with high performance liquid chromatography (HPLC). This information taken in concert with cation shifts will confirm our contention that ionic dysfunction and cellular edema occur as a result of mitochondrial impairment, and provide fresh avenues for therapeutic intervention. Finally, on the basis of this new understanding, we will evaluate the effectiveness of Cyclosporin A, a compound with known mitochondrial protective properties, in blunting the reduction of NAA and ATP, tissue cation changes and brain edema which occur with TBI. We will also evaluate the differential effect of FK- 506, a similar compound to CsA but with only calcineurin activity, to help dissect the mechanisms of mitochondrial protection